tbuckley/cabot-search huggingface dataset:
Olig1/2-Expressing Intermediate Lineage Progenitors Are Predisposed to PTEN/p53-Loss–Induced Gliomagenesis and Harbor Specific Therapeutic Vulnerabilities
Authors: Ravinder Verma, Xiameng Chen, Dazhuan Xin, Zaili Luo, Sean Ogurek, Mei Xin, Rohit Rao, Kalen Berry, Q. Richard Lu
Journal: Cancer Research (2023)

Abstract Malignant gliomas such as glioblastoma are highly heterogeneous with distinct cells of origin and varied genetic alterations. It remains elusive whether the specific states of neural cell lineages are differentially susceptible to distinct genetic alterations during malignant transformation. Here, an analysis of The Cancer Genome Atlas databases revealed that comutations of PTEN and TP53 are most significantly enriched in human high-grade gliomas. Therefore, we selectively ablated Pten and Trp53 in different progenitors to determine which cell lineage states are susceptible to malignant transformation. Mice with PTEN/p53 ablation mediated by multilineage-expressing human GFAP (hGFAP) promoter–driven Cre developed glioma but with incomplete penetrance and long latency. Unexpectedly, ablation of Pten and Trp53 in Nestin+ neural stem cells (NSC) or Pdgfra+/NG2+ committed oligodendrocyte precursor cells (OPC), two major cells of origin in glioma, did not induce glioma formation in mice. Strikingly, mice lacking Pten and Trp53 in Olig1+/Olig2+ intermediate precursors (pri-OPC) prior to the committed OPCs developed high-grade gliomas with 100% penetrance and short latency. The resulting tumors exhibited distinct tumor phenotypes and drug sensitivities from NSC- or OPC-derived glioma subtypes. Integrated transcriptomic and epigenomic analyses revealed that PTEN/p53-loss induced activation of oncogenic pathways, including HIPPO-YAP and PI3K signaling, to promote malignant transformation. Targeting the core regulatory circuitries YAP and PI3K signaling effectively inhibited tumor cell growth. Thus, our multicell state in vivo mutagenesis analyses suggests that transit-amplifying states of Olig1/2 intermediate lineage precursors are predisposed to PTEN/p53-loss–induced transformation and gliomagenesis, pointing to subtype-specific treatment strategies for gliomas with distinct genetic alterations. Significance: Multiple progenitor-state mutagenesis reveal that Olig1/2-expressing intermediate precursors are highly susceptible to PTEN/p53-loss–mediated transformation and impart differential drug sensitivity, indicating tumor-initiating cell states and genetic drivers dictate glioma phenotypes and drug responses. See related commentary by Zamler and Hu, p. 807
COPD in Africa: risk factors, hospitalisation, readmission and associated outcomes—a systematic review and meta-analysis
Authors: Chidiamara Maria Njoku, John R Hurst, Leigh Kinsman, Saliu Balogun, Kehinde Obamiro
Journal: Thorax (2023)

Background This review aims to synthesise available evidence on the prevalence of chronic obstructive pulmonary disease (COPD), associated risk factors, hospitalisations and COPD readmissions in Africa. Method Using the Met-Analyses and Systematic Reviews of Observational Studies guideline, electronic databases were searched from inception to 1 October 2021. The quality of studies was assessed using the Newcastle-Ottawa Scale. Evidence from retrieved articles was synthesised, and a random-effect model meta-analysis was conducted. The protocol was registered on PROSPERO. Results Thirty-nine studies met the inclusion criteria, with 13 included in the meta-analysis. The prevalence of COPD varied between the Global Initiative for Chronic Obstructive Lung Disease (2%–24%), American Thoracic Society/European Respiratory Society (1%–17%) and Medical Research Council chronic bronchitis (2%–11%) criteria, respectively. Increasing age, wheezing and asthma were consistent risk factors for COPD from studies included in the narrative synthesis. Our meta-analysis indicated that prior tuberculosis ((OR 5.98, 95% CI 4.18 to 8.56), smoking (OR 2.80, 95% CI: 2.19 to 3.59) and use of biomass fuel (OR 1.52, 95% CI: 1.39 to 1.67)) were significant risk factors for COPD. Long-term oxygen therapy (HR 4.97, 95% CI (1.04 to 23.74)) and frequent hospitalisation (≥3 per year) (HR 11.48, 95% CI (1.31 to 100.79)) were risk factors associated with 30-day COPD readmission. Conclusion This study not only highlights specific risk factors for COPD risk in Africa but also demonstrates the paucity and absence of research in several countries in a continent with substantial COPD-related mortality. Our findings contribute towards the development of evidence-based clinical guidelines for COPD in Africa. PROSPERO registration number CRD42020210581.
Identification of potent antimicrobial peptides via a machine-learning pipeline that mines the entire space of peptide sequences
Authors: Junjie Huang, Yanchao Xu, Yunfan Xue, Yue Huang, Xu Li, Xiaohui Chen, Yao Xu, Dongxiang Zhang, Peng Zhang, Junbo Zhao, Jian Ji
Journal: Nature Biomedical Engineering (2023)
Photoreceptor laminin drives differentiation of human pluripotent stem cells to photoreceptor progenitors that partially restore retina function
Authors: Hwee Goon Tay, Helder Andre, Vicki Chrysostomou, Swarnaseetha Adusumalli, Jing Guo, Xiaoyuan Ren, Wei Sheng Tan, Jia En Tor, Aida Moreno-Moral, Flavia Plastino, Hammurabi Bartuma, Zuhua Cai, Sai Bo Bo Tun, Veluchamy Amutha Barathi, Gavin Tan Siew Wei, Gianluca Grenci, Li Yen Chong, Arne Holmgren, Anders Kvanta, Jonathan Guy Crowston, Enrico Petretto, Karl Tryggvason
Journal: Molecular Therapy (2023)

Blindness caused by advanced stages of inherited retinal diseases and age-related macular degeneration are characterized by photoreceptor loss. Cell therapy involving replacement with functional photoreceptor-like cells generated from human pluripotent stem cells holds great promise. Here, we generated a human recombinant retina-specific laminin isoform, LN523, and demonstrated the role in promoting the differentiation of human embryonic stem cells into photoreceptor progenitors. This chemically defined and xenogen-free method enables reproducible production of photoreceptor progenitors within 32 days. We observed that the transplantation into rd10 mice were able to protect the host photoreceptor outer nuclear layer (ONL) up to 2 weeks post transplantation as measured by full-field electroretinogram. At 4 weeks post transplantation, the engrafted cells were found to survive, mature, and associate with the host's rod bipolar cells. Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses. Post-transplanted rabbit model also provided congruent evidence for synaptic connectivity with the degenerated host retina. The results may pave the way for the development of stem cell-based therapeutics for retina degeneration.
MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors
Authors: Michael Kilian, Ron Sheinin, Chin Leng Tan, Mirco Friedrich, Christopher Krämer, Ayelet Kaminitz, Khwab Sanghvi, Katharina Lindner, Yu-Chan Chih, Frederik Cichon, Benjamin Richter, Stefanie Jung, Kristine Jähne, Miriam Ratliff, Robert M. Prins, Nima Etminan, Andreas von Deimling, Wolfgang Wick, Asaf Madi, Lukas Bunse, Michael Platten
Journal: Cancer Cell (2023)
Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
Authors: Larry Mansouri, Birna Thorvaldsdottir, Lesley-Ann Sutton, Georgios Karakatsoulis, Manja Meggendorfer, Helen Parker, Ferran Nadeu, Christian Brieghel, Stamatia Laidou, Riccardo Moia, Davide Rossi, Mark Catherwood, Jana Kotaskova, Julio Delgado, Ana E. Rodríguez-Vicente, Rocío Benito, Gian Matteo Rigolin, Silvia Bonfiglio, Lydia Scarfo, Mattias Mattsson, Zadie Davis, Ajay Gogia, Lata Rani, Panagiotis Baliakas, Hassan Foroughi-Asl, Cecilia Jylhä, Aron Skaftason, Inmaculada Rapado, Fatima Miras, Joaquín Martinez-Lopez, Javier de la Serna, Jesús María Hernández Rivas, Patrick Thornton, María José Larráyoz, María José Calasanz, Viktória Fésüs, Zoltán Mátrai, Csaba Bödör, Karin E. Smedby, Blanca Espinet, Anna Puiggros, Ritu Gupta, Lars Bullinger, Francesc Bosch, Bárbara Tazón-Vega, Fanny Baran-Marszak, David Oscier, Florence Nguyen-Khac, Thorsten Zenz, Maria Jose Terol, Antonio Cuneo, María Hernández-Sánchez, Sarka Pospisilova, Ken Mills, Gianluca Gaidano, Carsten U. Niemann, Elias Campo, Jonathan C. Strefford, Paolo Ghia, Kostas Stamatopoulos, Richard Rosenquist
Journal: Leukemia (2023)
Multifunctional nanoparticle for cancer therapy
Authors: Yan Gao, Kaiyu Wang, Jin Zhang, Xingmei Duan, Qiu Sun, Ke Men
Journal: MedComm (2023)

Cancer is a complex disease associated with a combination of abnormal physiological process and exhibiting dysfunctions in multiple systems. To provide effective treatment and diagnosis for cancer, current treatment strategies simultaneously focus on various tumor targets. Based on the rapid development of nanotechnology, nanocarriers have been shown to exhibit excellent potential for cancer therapy. Compared with nanoparticles with single functions, multifunctional nanoparticles are believed to be more aggressive and potent in the context of tumor targeting. However, the development of multifunctional nanoparticles is not simply an upgraded version of the original function, but involves a sophisticated system with a proper backbone, optimized modification sites, simple preparation method, and efficient function integration. Despite this, many well-designed multifunctional nanoparticles with promising therapeutic potential have emerged recently. Here, to give a detailed understanding and analyzation of the currently developed multifunctional nanoparticles, their platform structures with organic or inorganic backbones were systemically generalized. We emphasized on the functionalization and modification strategies, which provide additional functions to the nanoparticle. We also discussed the application combination strategies that were involved in the development of nanoformulations with functional crosstalk. This review thus provides an overview of the construction strategies and application advances of multifunctional nanoparticles.
Risk factors for acquisition of carbapenemase-producing versus non-carbapenemase-producing enterobacterales: a case-control study
Authors: Nasreen Hassoun-Kheir, Khetam Hussein, Marianne Karram, Maram Saffuri, Sally Badaan, Shani Peleg, Marlieke E.A. de Kraker, Worood Aboelhega, Sigal Warman, Tamar Alon, Orna Eluk, Yuval Geffen, Mical Paul
Journal: Clinical Microbiology and Infection (2023)
International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood
Authors: Anita C S Hokken-Koelega, Manouk van der Steen, Margaret C S Boguszewski, Stefano Cianfarani, Jovanna Dahlgren, Reiko Horikawa, Veronica Mericq, Robert Rapaport, Abdullah Alherbish, Debora Braslavsky, Evangelia Charmandari, Steven D Chernausek, Wayne S Cutfield, Andrew Dauber, Asma Deeb, Wesley J Goedegebuure, Paul L Hofman, Elvira Isganatis, Alexander A Jorge, Christina Kanaka-Gantenbein, Kenichi Kashimada, Vaman Khadilkar, Xiao-Ping Luo, Sarah Mathai, Yuya Nakano, Mabel Yau
Journal: Endocrine Reviews (2023)

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.
Baseline Radiomic Signature to Estimate Overall Survival in Patients With NSCLC
Authors: Laurent Dercle, Matthew Fronheiser, Naiyer A. Rizvi, Matthew D. Hellmann, Sabine Maier, Wendy Hayes, Hao Yang, Pingzhen Guo, Tito Fojo, Lawrence H. Schwartz, Binsheng Zhao, David K. Leung
Journal: Journal of Thoracic Oncology (2023)

We aimed to define a baseline radiomic signature associated with overall survival (OS) using baseline computed tomography (CT) images obtained from patients with NSCLC treated with nivolumab or chemotherapy. The radiomic signature was developed in patients with NSCLC treated with nivolumab in CheckMate-017, -026, and -063. Nivolumab-treated patients were pooled and randomized to training, calibration, or validation sets using a 2:1:1 ratio. From baseline CT images, volume of tumor lesions was semiautomatically segmented, and 38 radiomic variables depicting tumor phenotype were extracted. Association between the radiomic signature and OS was assessed in the nivolumab-treated (validation set) and chemotherapy-treated (test set) patients in these studies. A baseline radiomic signature was identified using CT images obtained from 758 patients. The radiomic signature used a combination of imaging variables (spatial correlation, tumor volume in the liver, and tumor volume in the mediastinal lymph nodes) to output a continuous value, ranging from 0 to 1 (from most to least favorable estimated OS). Given a threshold of 0.55, the sensitivity and specificity of the radiomic signature for predicting 3-month OS were 86% and 77.8%, respectively. The signature was identified in the training set of patients treated with nivolumab and was significantly associated (p < 0.0001) with OS in patients treated with nivolumab or chemotherapy. The radiomic signature provides an early readout of the anticipated OS in patients with NSCLC treated with nivolumab or chemotherapy. This could provide important prognostic information and may support risk stratification in clinical trials.
Dengue, chikungunya and Zika virus infections among Dutch travellers to Suriname: a prospective study during the introduction of chikungunya and Zika virus, 2014 to 2017
Authors: Femke W Overbosch, Janke Schinkel, Amy Matser, Gerrit Koen, Irene Prange, Maria Prins, Gerard JB Sonder
Journal: Eurosurveillance (2023)

BackgroundSuriname, a country endemic for dengue virus (DENV), is a popular destination for Dutch travellers visiting friends and relatives and tourist travellers. Chikungunya and Zika virus (CHIKV, ZIKV) were introduced in 2014 and 2015, respectively. Data on infection risks among travellers are limited.AimWe aimed to prospectively study incidence rate (IR) and determinants for DENV, ZIKV and CHIKV infection in adult travellers to Suriname from 2014 through 2017.MethodsParticipants kept a travel diary and were tested for anti-DENV, anti-ZIKV and anti-CHIKV IgG antibodies (Euroimmun). Selected samples were subjected to an in-house DENV and ZIKV PRNT50. The IR (infections/1,000 person-months of travel) and IR ratio and determinants for infection were calculated.ResultsTravel-acquired infections were found in 21 of 481 participants: 18 DENV, four ZIKV and two CHIKV, yielding an IRDENV of 47.0 (95% CI: 29.6-74.6), IRZIKV of 11.6 (95% CI: 4.4-31.0) and IRCHIKV of 5.6 (95% CI: 1.4-22.2)/1,000 person-months. In nine DENV and three ZIKV infected participants, infections were PRNT50-confirmed, yielding a lower IRDENV of 23.3 (95% CI: 12.1-44.8) and an IRZIKV of 8.4 (95% CI: 2.7-26.1) per 1,000 person-months. Tourist travel was associated with DENV infection. ZIKV and CHIKV infections occurred soon after their reported introductions.ConclusionsDespite an overestimation of serologically confirmed infections, Dutch travellers to Suriname, especially tourists, are at substantial risk of DENV infection. As expected, the risk of contracting ZIKV and CHIKV was highest during outbreaks. Cross-reaction and potential cross-protection of anti-DENV and -ZIKV antibodies should be further explored.
Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia
Authors: Emily V. Wechsler, Nitin K. Ahuja, Darren Brenner, Walter Chan, Lin Chang, William D. Chey, Anthony J. Lembo, Baha Moshiree, Judy Nee, Shailja C. Shah, Kyle Staller, Eric D. Shah
Journal: Clinical Gastroenterology and Hepatology (2023)
Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection
Authors: Roberto Carnevale, Vittoria Cammisotto, Simona Bartimoccia, Cristina Nocella, Valentina Castellani, Marianna Bufano, Lorenzo Loffredo, Sebastiano Sciarretta, Giacomo Frati, Antonio Coluccia, Romano Silvestri, Giancarlo Ceccarelli, Alessandra Oliva, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni, Ombretta Turriziani, Martina Leopizzi, Giulia D’Amati, Pasquale Pignatelli, Francesco Violi
Journal: Circulation Research (2023)

Background: SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. Methods: We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B 2 , and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. Results: Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B 2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. Conclusions: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.
Genomic surveillance of SARS-CoV-2 positive passengers on flights from China to Italy, December 2022
Authors: Federica Novazzi, Emanuela Giombini, Martina Rueca, Andreina Baj, Lavinia Fabeni, Angelo Genoni, Francesca Drago Ferrante, Giulia Gramigna, Cesare Ernesto Maria Gruber, Sara Boutahar, Claudia Minosse, Ornella Butera, Renee Pasciuta, Daniele Focosi, Alberto Colombo, Andrea Antinori, Enrico Girardi, Francesco Vaia, Fabrizio Maggi
Journal: Eurosurveillance (2023)

With numbers of COVID-19 cases having substantially increased at the end of 2022 in China, some countries have started or expanded testing and genomic surveillance of travellers. We report screening results in Italy in late December 2022 of 556 flight passengers in provenance from two Chinese provinces. Among these passengers, 126 (22.7%) tested SARS-CoV-2 positive. Whole genome sequencing of 61 passengers’ positive samples revealed Omicron variants, notably sub-lineages BA.5.2.48, BF.7.14 and BQ.1.1, in line with data released from China.
Deep learning prediction of diffusion MRI data with microstructure-sensitive loss functions
Authors: Geng Chen, Yoonmi Hong, Khoi Minh Huynh, Pew-Thian Yap
Journal: Medical Image Analysis (2023)

Deep learning prediction of diffusion MRI (DMRI) data relies on the utilization of effective loss functions. Existing losses typically measure the signal-wise differences between the predicted and target DMRI data without considering the quality of derived diffusion scalars that are eventually utilized for quantification of tissue microstructure. Here, we propose two novel loss functions, called microstructural loss and spherical variance loss, to explicitly consider the quality of both the predicted DMRI data and derived diffusion scalars. We apply these loss functions to the prediction of multi-shell data and enhancement of angular resolution. Evaluation based on infant and adult DMRI data indicates that both microstructural loss and spherical variance loss improve the quality of derived diffusion scalars.
Systematic optimization of Cas12a base editors in wheat and maize using the ITER platform
Authors: Christophe Gaillochet, Alexandra Peña Fernández, Vera Goossens, Katelijn D’Halluin, Andrzej Drozdzecki, Myriam Shafie, Julie Van Duyse, Gert Van Isterdael, Camila Gonzalez, Mattias Vermeersch, Jonas De Saeger, Ward Develtere, Dominique Audenaert, David De Vleesschauwer, Frank Meulewaeter, Thomas B. Jacobs
Journal: Genome biology (2023)

Testing an ever-increasing number of CRISPR components is challenging when developing new genome engineering tools. Plant biotechnology has few high-throughput options to perform iterative design-build-test-learn cycles of gene-editing reagents. To bridge this gap, we develop ITER (Iterative Testing of Editing Reagents) based on 96-well arrayed protoplast transfections and high-content imaging.